DESCRIPTION (provided by application): Cardiovascular disease (CVD) is the leading cause of death in women in the United States. Epidemiological studies have demonstrated that preeclampsia could identify women at increased risk to develop hypertension,coronary artery disease, diabetes, and stroke later in life. However, preeclampsia is unlikely to be associated with a single causative factor and shares common pathogenic features with CVD, including endothelial dysfunction, thrombophilic predisposition, alterations in insulin sensitivity, hypertriglyceridemia, and proinflammatory changes. Therefore, some women may have underlying risk factors for CVD that also predispose them to preeclampsia. Obesity is a common risk factor for both. C-reactive protein, a marker for inflammation, is increased in both conditions. Plasma leptin levels are elevated even before preeclampsia is clinically evident, suggesting that the obese gene may be involved. Recent reports support a role for abnormal angiogenesis in the development of preeclampsia. The soluble Flt1 (sFlt1) is the soluble form of the vascular endothelial growth factor (VEGF) receptor 1, which binds VEGF and other angiogenic factors in the circulation, thereby decreasing their action. Based on prior reports, we successfully characterized and refined an animal model of preeclampsia by transfecting mice with an adenovirus carrying sFlt1. This model is characterized by elevated blood pressure, placental hypoxia, vascular, hematological, hepatic, and renal changes in response to overexpression of sFlt1 during pregnancy. We have also followed these animals postpartum. In preliminary experiments performed in mice 6 to 8 months after delivery, we did not find differences in the vascular reactivity in vitro, nor blood pressure in vivo, between mice injected with control virus mFc or saline and mice that had sFlt1-induced preeclampsia. Therefore, we hypothesize that pregnancy complications superimposed on CVD risk factors, such as obesity, lead to the development of long-term adverse changes in the maternal vasculature. To test this hypothesis, we propose the following aims: (1) to determine vascular function in pregnant mice with preexisting obesity, with or without sFlt1-induced preeclampsia, and compare with that in pregnant mice on a regular diet, with or without sFlt1-induced preeclampsia;and (2) to examine the long-term cardiovascular vascular function in mice with or without pre-pregnancy obesity, and with or without sFlt1- induced preeclampsia. Comparison of vascular function in pregnanct and postpartum animals in this model will shed light on the importance of preexisting conditions versus preeclampsia and their interaction in the development of maternal CVD. This model will also provide an experimental tool for investigating mechanisms of CVD and the well established gender differences in health and disease.